WO2005044175A2 - Desensibilisation de l'activation du complement a l'aide de composes inhibiteurs de monocytes/macrophages - Google Patents

Desensibilisation de l'activation du complement a l'aide de composes inhibiteurs de monocytes/macrophages Download PDF

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Publication number
WO2005044175A2
WO2005044175A2 PCT/IB2004/003620 IB2004003620W WO2005044175A2 WO 2005044175 A2 WO2005044175 A2 WO 2005044175A2 IB 2004003620 W IB2004003620 W IB 2004003620W WO 2005044175 A2 WO2005044175 A2 WO 2005044175A2
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WO
WIPO (PCT)
Prior art keywords
therapeutic agent
bisphosphonate
complement
patient
alendronate
Prior art date
Application number
PCT/IB2004/003620
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English (en)
Other versions
WO2005044175A3 (fr
Inventor
Gershon Golomb
Hila Epstein
Original Assignee
Biorest Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biorest Ltd. filed Critical Biorest Ltd.
Priority to JP2006538981A priority Critical patent/JP2007510711A/ja
Priority to CA002542602A priority patent/CA2542602A1/fr
Priority to AU2004287277A priority patent/AU2004287277A1/en
Priority to EP04798779A priority patent/EP1680130A4/fr
Publication of WO2005044175A2 publication Critical patent/WO2005044175A2/fr
Publication of WO2005044175A3 publication Critical patent/WO2005044175A3/fr
Priority to IL175064A priority patent/IL175064A0/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to methods and compositions designed for the prevention, reduction, treatment, or management of complement activation-related acute hypersensitivity also known as C- mediated pseudoallergy (CARPA).
  • CARPA complement activation-related acute hypersensitivity also known as C- mediated pseudoallergy (CARPA).
  • CARPA complement activation-related acute hypersensitivity also known as C- mediated pseudoallergy
  • CARPA associated with administration of a medicinal composition including, but not limited to, those compositions in liposomal, micellar, nanoparticle, emulsion, and colloidal formulations is prevented, reduced, treated, or managed.
  • the therapeutic agent specifically targets macrophages and/or monocytes. Because macrophages and monocytes are phagocytic cells, in these embodiments, the therapeutic agents are prepared such that they comprise particles of such properties as to enter into a cell primarily or exclusively via phagocytosis.
  • the therapeutic agent comprises an active compound in a formulation such that the physiochemical properties, e.g. size or charge, of the formulation can be internalized only or primarily by phagocytosis.
  • the therapeutic agent may comprise an encapsulated active compound or a particulate active compound.
  • the present invention relates to a method of preventing, reducing, treating, or managing CARPA by administering to an individual in need thereof an effective amount of one or more therapeutic agents comprising an encapsulated active compound.
  • the present invention relates to a method of preventing, reducing, treating, or managing CARPA by administering to an individual in need thereof an effective amount of one or more therapeutic agents comprising a particulate active compound.
  • the active compound is encapsulated in a suitable carrier of a specific dimension or made into particulates of a specific dimension.
  • the present invention includes a pharmaceutical composition for administration to subjects in need thereof a therapeutic agent comprising an active compound in a formulation selected from the group consisting of an encapsulated active compound and a particulate active compound together with a pharmaceutically acceptable vehicle, carrier, stabilizer or diluent for the prevention, reduction, treatment, or management of CARPA.
  • a pharmaceutically acceptable vehicle, carrier, stabilizer or diluent for the prevention, reduction, treatment, or management of CARPA.
  • the therapeutic agent of the present invention comprises an active compound in a formulation that is preferably in the size range of 0.03- 1.O ⁇ m.
  • the more preferred ranges include, but are not limited to, 0.07-0.5 ⁇ m, 0.1-0.3 ⁇ m and 0.1 to 0.18 ⁇ m.
  • the present invention relates to methods and compositions designed for the prevention, reduction, treatment, or management of complement activation-related acute hypersensitivity also known as C- mediated pseudoallergy (CARPA).
  • CARPA complement activation-related acute hypersensitivity also known as C- mediated pseudoallergy
  • the complement system causes hypersensitivity reactions with the help of macrophages and monocytes. During these reactions, massive increases in macrophage/monocyte secretion products are observed in the blood of the affected patient.
  • the present invention relates to methods and compositions designed to decrease or inhibit the activity of and/or eliminate or diminish the amount of macrophages and/or monocytes for an acute, short term period preceding, during, or following administration of a complement-activating medicinal composition such that the medicinal composition can be tolerated by the patient.
  • the methods of the invention comprise the administration of an effective amount of a formulation containing one or more therapeutic agents which specifically decreases or inhibits the activity of and/or eliminates or diminishes the amount of macrophages and/or monocytes in a patient.
  • the therapeutic agents used in the methods of the invention specifically decrease or inhibit the activity of macrophages and/or monocytes and/or eliminate or diminish the amount of macrophages and/or monocytes in a patient.
  • Specificity of the therapeutic agents is due to the formulation of the active compound in the therapeutic agent such that the active compound has the ability to affect only particular cell types (e.g., macrophages and/or monocytes).
  • specificity of the formulation for phagocytic cells is due to the physiochemical properties ,e.g. size or charge, of the formulation such that it can only or primarily be internalized by phagocytosis.
  • phagocytosis refers to a preferred means of entry into a phagocytic cell and is well understood in the art. However, the term should be understood to also encompass other forms of endocytosis which may also accomplish the same effect. In particular, it is understood that receptor-mediated endocytosis and other cellular means for absorbing/internalizing material from outside the cell are also encompassed by the methods and compositions of the present invention.
  • active compounds refers to molecules which are encapsulated or particularized to make up all or part of the therapeutic agent and provide the inactivating/toxic potency to the formulation, e.g., inhibits or decreases macrophage and/or monocyte activity and/or eliminates or decreases the amount of macrophages and/or monocytes.
  • Ri is H, OH or a halogen atom; and R 2 is halogen; linear or branched C-i-C-io alkyl or C 2 -C ⁇ o alkenyl optionally substituted by heteroaryl or heterocyclyl C 1 -C 10 alkylamino or C 3 -Ca cycloalkylamino where the amino may be a primary, secondary or tertiary; -NHY where Y is hydrogen, C 3 -C ⁇ cycloalkyl, aryl or heteroaryl; or R 2 is -SZ where Z is chlorosubstituted phenyl or pyridinyl.
  • risedronate 3-[N-(2- phenylthioethyl)-N-methylamino]-l-hydroxypropane-1 ,1-bishosphonic acid; 1- hydroxy-3-(pyrrolidin-1-yl)propane-1 ,1-bisphosphonic acid, 1-(N- phenylaminothiocarbonyl)methane-l,l-diphosphonic acid, e.g. FR 78844 (Fujisawa); 5-benzoyl-3,4-dihydro-2H-pyrazole-3,3-diphosphonic acid tetraethyl ester, e.g.
  • the present invention also encompasses therapeutic agents containing other active compounds including, but not limited to, gallium, gold, selenium, gadolinium, silica, mithramycin, sirolimus, everolimus, and other similar analogs thereof.
  • the present invention is meant to encompass the administration of one or more therapeutic agents to prevent, reduce, treat, or manage complement activation-related acute hypersensitivity also known as C- mediated pseudoallergy (CARPA). More than one therapeutic agent can be administered in combination to the patient.
  • the therapeutic agents administered in combination may have different active compounds in the same or different formulation (e.g., encapsulated or particulate) or the same active compound in different formulations.
  • the term "in combination" is not limited to the administration of the therapeutic agents at exactly the same time, but rather it is meant that the therapeutic agents are administered to a patient in a sequence and within a time interval such that they can act together to provide an increased benefit than if they were administered otherwise.
  • the methods of screening for active compounds generally involve incubating a candidate therapeutic agent with phagocytic cells (e.g., macrophages and/or monocytes) either in vitro or in vivo and then assaying for an alteration (e.g., decrease) in phagocytic cell activity or longevity thereby identifying an active compound for use in the present invention.
  • phagocytic cells e.g., macrophages and/or monocytes
  • Any method known in the art can be used to assay phagocytic cell activity or longevity.
  • an agent that decreases the activity of phagocytes is identified by: a) contacting a phagocyte with a first agent and a second agent, said first agent being an agent which activates said phagocyte and said second agent being a candidate agent; and b) determining the level of activation in said contacted phagocyte, wherein a decrease in activation in said contacted phagocyte as compared to the level of activation in a phagocyte contacted with said first agent in the absence of said second agent (i.e., a control cell) indicates that said second agent decreases the activity of a phagocyte.
  • an agent that decreases the amount of phagocytes is identified by: a) contacting a phagocyte with an agent; and b) determining the viability of said contacted phagocyte, wherein a decrease in viability in said contacted phagocyte as compared to the viability of a phagocyte not contacted with said agent (i.e., a control cell) indicates that said agent decreases phagocytes.
  • candidate agents may be used in animal models of
  • CARPA to assess their ability to be used in the methods of the invention.
  • Animal models may be used as a first assay to determine if a candidate agent may be used as an active agent as well as a second assay to confirm the utility of agents found to have desirable activity in in vitro assays.
  • the animal model used is a pig CARPA model (see e.g., Section 6).
  • Intravenous injections of small amounts of certain liposomes in pigs leads instantly to significant hemodynamic and cardiopulmonary changes and skin alterations typical of anaphylactic or anaphylactoid shock.
  • the reaction is associated with massive rises of macrophage secretion products (especially TXA 2 ) in the blood. These reactions can be lethal without resuscitation with epinephrine, cardiac massage, and/or electroshock.
  • This reaction in pigs closely resembles the hypersensitivity syndrome observed in a relatively high proportion (2-45%) of humans after infusion of certain liposomal and anticancer drugs.
  • the bolus dose of Doxil that causes cardiopulmonary distress in pigs corresponds to the dose that reaches the human blood during the first 20-60 seconds of infusion and causes CARPA in sensitive individuals.
  • liposome-induced CARPA in pigs shows relatively small biological variation (e.g., essentially all pigs react similarly to a certain reactogenic liposome preparation) thus the model is highly reproducible.
  • Therapeutic agents comprise active compounds in formulations such that the active compound is in particles that are large enough to only or primarily be internalized by phagocytosis, thus imparting specificity to macrophages and monocytes. Although non-phagocytic cells may be affected by the active compound should it become intracellular, there is no mechanism for a non-phagocytic cell to internalize the active compound when formulated in this manner (i.e., as a therapeutic agent). Therapeutic agents comprise active compounds formulated preferably in the size range of 0.03- 1.0 ⁇ m, more preferably 0.07-0.5 ⁇ m, more preferably 0.1-0.3 ⁇ m, and more preferably 0.1-0.18 ⁇ m. However, this is merely an example and other size ranges may be used without departing from the spirit or scope of the invention.
  • any method known in the art can be used to incorporate an active compound into a formulation such that it can only or primarily be internalized via phagocytosis.
  • Formulations of active compounds i.e., therapeutic agents
  • formulations of active compounds may discharge the compound from the particles when they are within the target cell (e.g., the macrophage or monocyte) at the target site.
  • the target cell e.g., the macrophage or monocyte
  • the active compound is encapsulated in a carrier (i.e., encapsulating agent) of desired properties.
  • a carrier i.e., encapsulating agent
  • encapsulated active compound includes an active compound which is encapsulated, embedded, and/or adsorbed within particle, dispersed in the particle matrix, adsorbed or linked on a surface of the particle, or a combination of any of these forms.
  • the particles include, but are not limited to, inert polymeric particles, such as microcapsules, nanocapsules, nanospheres, microspheres, nanoparticles, microparticles, and liposomes.
  • the encapsulating agent is a liposome.
  • the liposomes may be prepared by any of the methods known in the art (see, e.g., M ⁇ nkkonen, J. et al., 1994, J. Drug Target, 2:299-308; M ⁇ nkkonen, J. et al., 1993, Calcif. Tissue Int., 53:139-145; Lasic DD., Liposomes Technology Inc., Elsevier, 1993, 63-105. ( chapter 3); Winterhalter M, Lasic DD, Chem Phys Lipids, 1993 Sep;64(1-3):35-43).
  • the liposomes may be positively charged, neutral or, more preferably, negatively charged.
  • the liposomes may be a single lipid layer or may be multilamellar. Suitable liposomes in accordance with the invention are preferably non-toxic liposomes such as, for example, those prepared from phosphatidyl-choline phosphoglycerol and cholesterol.
  • the diameter of the liposomes used preferably ranges from 0.03-1.O ⁇ m, and more preferably 100-300nm. However, other size ranges suitable for phagocytosis by macrophages and/or monocytes may also be used.
  • the encapsulating agent is an embedding agent such that the active compound is embedded in a carrier of desired properties.
  • An active compound which is encapsulated by embedding includes those active compounds that are embedded, enclosed, and/or adsorbed within a carrier, dispersed in the carrier matrix, adsorbed or linked on the carrier surface, or a combination of any of these forms.
  • the embedding agent (or carrier) is a microparticle, nanoparticle, nanosphere, microsphere, microcapsule, or nanocapsule (see e.g., M. Donbrow in: Microencapsulation and Nanoparticles in Medicine and Pharmacy. CRC Press, Boca Raton, FL, 347, 1991 ).
  • the therapeutic agent is in particulate form, the particles each being of desired properties.
  • a particulate active compound includes any insoluble suspended or dispersed particulate form of the active compound which is not encapsulated, entrapped or absorbed within a carrier.
  • An active compound which is in particulate form includes those active compounds that are suspended or dispersed colloids, aggregates, flocculates, insoluble salts, insoluble complexes, and polymeric chains of an agent.
  • Such particulates are insoluble in the fluid in which they are stored/administered (e.g., saline or water) as well as the fluid in which they provide their therapeutic effect (e.g., blood or serum).
  • insoluble refers to a solubility of one (1 ) part of a particulate active compound in more than ten-thousand (10,000) parts of a solvent. Any method known in the art to make particulates or aggregates can be used. Preferably, particulates are 0.03-1. O ⁇ m in diameter and can be any particular shape.
  • any method known in the art can be used to determine the size of the particles in the therapeutic agent before administration to a patient in need thereof.
  • a Nicomp Submicron Particle Sizer model 370,
  • methods and compositions of the present invention are used to prevent, decrease, treat, or manage CARPA caused by administration of any complement-activating medicinal composition.
  • a medicinal composition is complement-activating if administration of a therapeutically effective amount of the composition causes the activation of complement via the classical pathway, the alternative pathway, or any combination of each.
  • a hypersensitivity reaction e.g., CARPA
  • a medicinal composition is complement activating if, after administration of said medicinal composition to a patient, the patient experiences one or more of the following symptoms: cardiopulmonary distress (e.g., dyspnea, tachypnea, tachcardia, chest pain, back pain, etc.), alteration in blood pressure, increased pulmonary arterial pressure, alteration in systemic arterial pressure, increased heart rate, decreased cardiac output, decreased PCO 2 in exhaled air, decreased capillary PO 2 , increased pulmonary and systemic vascular resistance, flare or flushing of the skin, and EKG alterations (e.g., tachycardia, bradycardia, arrhythmia, ST-depression, T- wave inversion) or the like.
  • cardiopulmonary distress e.g., dyspnea, tachypnea, tachcardia, chest pain, back pain, etc.
  • alteration in blood pressure increased pulmonary arterial pressure
  • alteration in systemic arterial pressure increased heart rate
  • cardiac output decreased PCO 2 in exhaled air
  • the patient administered a therapeutic agent or pharmaceutical composition thereof has not yet had a CARPA episode but is undergoing treatment with a known complement-activating medicinal composition.
  • the patient administered a therapeutic agent or pharmaceutical composition thereof is at risk for developing CARPA (either due to administration of a complement-activating medicinal composition or otherwise).
  • a therapeutic agent or pharmaceutical composition thereof is administered to a patient at the same time or substantially the same time as the administration of a complement-activating medicinal composition.
  • the patient has had a prior CARPA episode in response to a prior administration of a medicinal composition and/or the patient is undergoing treatment with a known complement-activating medicinal composition and/or the patient is at risk for developing CARPA.
  • the therapeutic agent or pharmaceutical composition thereof and the medicinal composition are administered within 10 minutes of each other.
  • the therapeutic agent or pharmaceutical composition thereof and the medicinal composition that is liposomal are mixed together and administered as one composition.
  • the therapeutic agent or pharmaceutical composition thereof and the medicinal composition are mixed together and encapsulated in the same liposomes when liposomal formulations of medicinal compositions are administered.
  • the skilled person can readily determine the appropriate dose and timing of administration depending on various physiological factors specific to the individual patient (such as, for example, weight, medical history and genetic predisposition), various factors which influence the anticipated risk of CARPA (such as the type of medicinal composition administered), and the type of formulation being used (e.g., encapsulated, embedded, particulate, etc.).
  • various physiological factors specific to the individual patient such as, for example, weight, medical history and genetic predisposition
  • various factors which influence the anticipated risk of CARPA such as the type of medicinal composition administered
  • the type of formulation being used e.g., encapsulated, embedded, particulate, etc.
  • the protocols and compositions of the invention are preferably tested in vitro, and then in vivo, for the desired therapeutic activity, prior to use in humans.
  • an in vitro assay is an in vitro cell culture assay in which phagocytes (e.g., macrophages and/or monocytes) are grown in culture, and exposed to or otherwise administered a therapeutic agent, and observed for an effect of this assay upon the cells, e.g., inhibited or decreased activity and/or complete or partial cell death.
  • the phagocytic cells may be obtained from an established cell line or recently isolated from an individual as a primary cell line.
  • macrophage/monocyte activation can be assayed by quantitating the levels of chemotactic factors such as macrophage chemoattractant protein-1 (MCP-1 ), interleukin 1 beta (IL-1 ⁇ ), tissue necrosis factor alpha (TNF- ⁇ ) and macrophage inflammatory protein-1 alpha (MIP-1 alpha).
  • MCP-1 macrophage chemoattractant protein-1
  • IL-1 ⁇ interleukin 1 beta
  • TNF- ⁇ tissue necrosis factor alpha
  • MIP-1 alpha macrophage inflammatory protein-1 alpha

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Abstract

La présente invention se rapporte à des procédés et des compositions conçus pour la prophylaxie, la réduction, le traitement ou la prise en charge de l'hypersensibilité aiguë liée à l'activation du complément, également appelée pseudoallergie à médiation C (CARPA), provoquée par l'administration d'une composition médicamenteuse et notamment mais non exclusivement des compositions des formulations liposomales, micellaires, nanoparticulaires, émulsionnées et colloïdales. Les procédés selon l'invention consistent à administrer une quantité efficace d'un ou plusieurs agents thérapeutiques renfermant un ou plusieurs composés actifs qui provoquent une diminution ou inhibition spécifique de l'activité des macrophages et/ou des monocytes, et/ou qui provoquent l'élimination ou une réduction de la quantité de macrophages et/ou de monocytes. Selon les modes préférés de réalisation, le composé actif est un bisphosphonate.
PCT/IB2004/003620 2003-11-07 2004-11-05 Desensibilisation de l'activation du complement a l'aide de composes inhibiteurs de monocytes/macrophages WO2005044175A2 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2006538981A JP2007510711A (ja) 2003-11-07 2004-11-05 単球／マクロファージ阻害化合物を用いる補体活性化の脱感作
CA002542602A CA2542602A1 (fr) 2003-11-07 2004-11-05 Desensibilisation de l'activation du complement a l'aide de composes inhibiteurs de monocytes/macrophages
AU2004287277A AU2004287277A1 (en) 2003-11-07 2004-11-05 Desensitization of complement activation using monocyte/macrophage inhibitory compounds
EP04798779A EP1680130A4 (fr) 2003-11-07 2004-11-05 Desensibilisation de l'activation du complement a l'aide de composes inhibiteurs de monocytes/macrophages
IL175064A IL175064A0 (en) 2003-11-07 2006-04-20 Desensitization of complement activation using monocyte/macrophage inhibitory compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US51840503P 2003-11-07 2003-11-07
US60/518,405 2003-11-07

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WO2005044175A2 true WO2005044175A2 (fr) 2005-05-19
WO2005044175A3 WO2005044175A3 (fr) 2005-07-14

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US (1) US20050153937A1 (fr)
EP (1) EP1680130A4 (fr)
JP (1) JP2007510711A (fr)
CN (1) CN1878559A (fr)
AU (1) AU2004287277A1 (fr)
CA (1) CA2542602A1 (fr)
IL (1) IL175064A0 (fr)
WO (1) WO2005044175A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
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EP1906963A2 (fr) * 2005-07-26 2008-04-09 Biorest Ltd. Procede de traitement de lesion d'ischemie-reperfusion
EP2213314A1 (fr) * 2009-01-30 2010-08-04 Biotronik VI Patent AG Implant à base d'un alliage biocorrodable de magnésium
US9498488B2 (en) 2003-06-27 2016-11-22 Biorest Ltd. Method of treating acute coronary syndromes
US9993427B2 (en) 2013-03-14 2018-06-12 Biorest Ltd. Liposome formulation and manufacture

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US20080181928A1 (en) * 2006-12-22 2008-07-31 Miv Therapeutics, Inc. Coatings for implantable medical devices for liposome delivery
WO2009048645A2 (fr) * 2007-10-10 2009-04-16 Miv Therapeutics, Inc. Revêtements lipidiques pour des dispositifs médicaux implantables
US20090215729A1 (en) * 2008-02-19 2009-08-27 Johnson Erin M Microparticle compositions to modify cancer promoting cells
WO2018119115A1 (fr) 2016-12-21 2018-06-28 Protiva Biotherapeutics, Inc. Procédés pour améliorer des réactions de perfusion
CN111265480B (zh) * 2018-12-04 2022-10-21 石药集团中奇制药技术（石家庄）有限公司 一种表柔比星脂质体及其制备方法

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IL125336A0 (en) * 1998-07-14 1999-03-12 Yissum Res Dev Co Compositions for inhibition and treatment of restinosis
US6984400B2 (en) * 1998-07-14 2006-01-10 Yissum Research Development Company Of The Hebrew University Of Jerusalem Method of treating restenosis using bisphosphonate nanoparticles

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9498488B2 (en) 2003-06-27 2016-11-22 Biorest Ltd. Method of treating acute coronary syndromes
US9827254B2 (en) 2003-06-27 2017-11-28 Biorest Ltd. Method of treating acute coronary syndromes
US10213446B2 (en) 2003-06-27 2019-02-26 Biorest Ltd. Method of treating acute coronary syndromes
US10517883B2 (en) 2003-06-27 2019-12-31 Zuli Holdings Ltd. Method of treating acute myocardial infarction
EP1906963A2 (fr) * 2005-07-26 2008-04-09 Biorest Ltd. Procede de traitement de lesion d'ischemie-reperfusion
EP1906963A4 (fr) * 2005-07-26 2009-11-11 Biorest Ltd Procede de traitement de lesion d'ischemie-reperfusion
EP2213314A1 (fr) * 2009-01-30 2010-08-04 Biotronik VI Patent AG Implant à base d'un alliage biocorrodable de magnésium
US8268235B2 (en) 2009-01-30 2012-09-18 Biotronik Vi Patent Ag Implant with a base body of a biocorrodible magnesium alloy
US9993427B2 (en) 2013-03-14 2018-06-12 Biorest Ltd. Liposome formulation and manufacture
US10265269B2 (en) 2013-03-14 2019-04-23 Biorest Ltd. Liposome formulation and manufacture
US11633357B2 (en) 2013-03-14 2023-04-25 Zuli Holdings, Ltd. Liposome formulation and manufacture

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EP1680130A4 (fr) 2008-03-12
JP2007510711A (ja) 2007-04-26
US20050153937A1 (en) 2005-07-14
WO2005044175A3 (fr) 2005-07-14
EP1680130A2 (fr) 2006-07-19
CA2542602A1 (fr) 2005-05-19
IL175064A0 (en) 2008-04-13
AU2004287277A1 (en) 2005-05-19
CN1878559A (zh) 2006-12-13

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